Cheminfomatic-based Drug Discovery of Human Tyrosine Kinase Inhibitors.
Cheminfomatic-based Drug Discovery of Human Tyrosine Kinase Inhibitors.
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DOI：
10.2174/1568026615666150915120814
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发表时间：
2016
影响因子：
3.4
通讯作者：
Simon Wang X
中科院分区：
文献类型：
--
作者：
Reid TE;Fortunak JM;Wutoh A;Simon Wang X
受体酪氨酸激酶(RTK)是调节细胞生长、增殖、分化、存活和新陈代谢过程中细胞间信号和通讯事件的重要组成部分。RTK及其相关信号通路的解除调控可导致多种人类疾病，如免疫缺陷、糖尿病、动脉硬化、牛皮癣和癌症。因此，RTK已成为近十年来最重要的药物靶标家族之一。制药公司一直致力于发现RTK的小分子抑制剂，其中许多已经获得美国食品和药物管理局(US FDA)的批准，或目前正在进行临床试验。RTKs小分子抑制剂开发的巨大成功在很大程度上归功于使用现代化学信息学方法来识别铅支架。这些包括定量结构-活性关系(QSAR)建模，以及在这种情况下基于结构和配体的药效团建模技术。在此，我们彻底查阅了文献，试图对已知的活性RTK抑制剂的基本结构-活性关系(SARS)/药效团特征的主要发现进行比较分析，其中大多数是从化学信息学建模方法收集的。
Receptor Tyrosine Kinases (RTKs) are essential components for regulating cell-cell signaling and communication events in cell growth, proliferation, differentiation, survival and metabolism. Deregulation of RTKs and their associated signaling pathways can lead to a wide variety of human diseases such as immunodeficiency, diabetes, arterosclerosis, psoriasis and cancer. Thus RTKs have become one of the most important drug targets families in recent decade. Pharmaceutical companies have dedicated their research efforts towards the discovery of small-molecule inhibitors of RTKs, many of which had been approved by the U.S. Food and Drug Administration (US FDA) or are currently in clinical trials. The great successes in the development of small-molecule inhibitors of RTKs are largely attributed to the use of modern cheminformatic approaches to identifying lead scaffolds. Those include the quantitative structure-activity relationship (QSAR) modeling, as well as the structure-, and ligand-based pharmacophore modeling techniques in this case. Herein we inspected the literature thoroughly in an effort to conduct a comparative analysis of major findings regarding the essential structure-activity relationships (SARs)/pharmacophore features of known active RTK inhibitors, most of which were collected from cheminformatic modeling approaches.